Prostaglandin E{HD 2 {B and derivatives for reducing the side effects of anti-inflammatory agents

ABSTRACT

A method is disclosed for inhibiting and alleviating gastrointestinal side effects often encountered during therapy with antiinflammatory agents such as indomethacin, phenylbutazone, oxyphenylbutazone and the like. The method comprises the administration of prostaglandin E2, 15methylprostaglandin E2, 16-methylprostaglandin E2 or 16,16dimethylprostaglandin E2 or their corresponding lower alkyl esters to a mammal receiving such therapy. Also disclosed are useful pharmaceutical compositions for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose of prostaglandin E2, 15-methylprostaglandin E2, 16-methylprostaglandin E2 or 16,16dimethylprostaglandin E2 or their corresponding lower alkyl esters and a therapeutic dose of an antiinflammatory agent.

A United States Patent 1191 Lippmann Dec. 16, 1975 PROSTAGLANDIN E AND DERIVATIVES FOR REDUCING THE SIDE EFFECTS OF ANTI-INFLAMMATORY AGENTS [75] Inventor: Wilbur Lippmann, Montreal,

Canada [73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: July 10, 1973 [21] Appl. No.: 378,113

OTHER PUBLICATIONS Physicians Desk Reference2lst Edition (1967) p. 870.

Robert et al., -Prostaglandin Bibliograpy (1971) p. 41.

Primary Examine'rSam Rosen Attorney, Agent, or Firm-John P. Floyd [57] ABSTRACT A method is disclosed for inhibiting and alleviating gastrointestinal side effects often encountered during therapy with antiinflammatory agents such as indomethacin, phenylbutazone, oxyphenylbutazone and the like. The method comprises the administration of prostaglandin E IS-methylpro staglandin E l6-methylprostaglandin E or 16 l6-dimethylprostaglandin E or their corresponding lower alkyl esters to a mammal receiving such therapy.

Also disclosed are useful pharmaceutical compositions for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose of prostaglandin E IS-methylprostaglandin E 1 6-methylprostaglandin E or l6,16-dimethylprostaglandin E or their corresponding lower alkyl esters and a therapeutic dose of an antiinflammatory agent.

8 Claims, No Drawings PROSTAGLANDIN E AND DERIVATIVES FOR REDUCING THE SIDE EFFECTS OF ANTI-INFLAMMATORY AGENTS BACKGROUND OF THE INVENTION 1. Field of Invention This invention relates to a method and to compositions for reducing or treating gastrointestinal side ef-. fects caused by antiinflammatory agents. More particularly, this invention relates to the finding that the administration of certain prostaglandin-type substances to a mammal inhibits and alleviates the gastrointestinal side effects, for example, ulceration, gastrointestinal bleeding, epigastric distress, diarrhea, melena and the like, associated with antiinflammatory drug therapy.

2. Background of the Invention Antiinflammatory agents, for example, indomethacin, phenylbutazone, oxyphenylbutazone, aspirin and the like, are useful for the treatment of arthritic and rheumatic diseases. However, the use of these agents is associated with a rather high incidence of side effects, the most serious being those related to gastrointestinal reactions. In fact, it has been stated that one of the most common reasons for discontinuing therapy with such agents is the development of a peptic ulcer.

Realizing the serious drawback of this form of therapy, Y. H. Lee, et al., Arch. Int. Pharrnacodyn. Ther., 192, 370 1971), administered various known antiulcer compounds to rats treated with a gastric ulcer-producing dose of indomethacin to evaluate the possible utility of several types of antiulcer compounds in reducing the ulcerogenic activity of indomethacin. Some of the compounds evaluated, for example propantheline bromide, proved to be effective but only when administered at doses much higher than their usual therapeutic dose.

In a related development it has been suggested that certain prostaglandin derivatives may be of value for the treatment of peptic ulcers. This suggestion is based on the finding that prostaglandin E and several of its analogs inhibit gastric acid secretion; for example, see W. Lippmann, Ann. NY. Acad. Sci., 180, 332 (1971).

In view of the foregoing the finding of the present disclosure is surprising and interesting indeed. Namely, it has been found that the prostaglandin-type substances of the present disclosure inhibit ulcer formation and alleviate the symptoms concerned therewith at doses substantially less than those required for the inhibition of the basal secretion of gastric acid.

This finding is even more surprising in light of the finding that similar inhibition and treatment of aspirininduced ulcers is achieved at doses of prostaglandintype substances which are substantially more than required for the inhibition of basal secretion of gastric acid.

Furthermore, other gastrointestinal disturbances associated with the antiinflammatory agents are antagonized and minimized.

SUMMARY OF THE INVENTION According to the method of this invention an effective gastrointestinal side-effect inhibiting amount of prostaglandin E IS-methylprostaglandin E 16- methylprostaglandin E or l6,l6-dimethylprostaglandin E or their corresponding lower alkyl esters is administered to an antiinflammatory agent-treated Enamtreating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose of prostaglandin E IS-methylprostaglandin E 16- methylprostaglandin E or 16,16-dimethylprostaglandin E or their corresponding lower alkyl esters and a therapeutic dose of an antiinflammatory agent.

DETAILS OF THE INVENTION The active prostaglandin-type substances (prostaglandin substances) of this invention are prostaglandin E (PGE trans, cis-7-[3-hydroxy-2-(3-hydroxy-loctenyl )-5-oxocyclopentyll-5-heptenoic acid, I 5- methylprostaglandin E (IS-methyl PGE trans, cis-[3- hydroxy-2-( 3-hydroxy-3-methyl- 1-0ctenyl)-5-oxocyclopentyl]-5-heptenoic acid), l6-methylprostaglandin E (l6-methyl PGE trans, cis-7-[3-hydroxy-2-(3- hydroxy-4-methyll-octenyl )-5-oxocyclopentyl -5- heptenoic acid), 16,l6-dimethylprostaglandin E (16,16-dimethyl PGE trans, cis-7-[3-hydroxy-2-(3- hydroxy-4 ,4-dimethyll -octenyl )-5-oxocyclopentyl J -5- heptenoic acid), and their corresponding lower alkyl esters, particularly the corresponding methyl, ethyl and propyl esters.

Also included within the scope of this invention are the pharmaceutically acceptable salts of the acid specie of the above prostaglandin-type substances. These salts possess the same activity as the parent acid and are included within the scope of this invention. The acid is transformed in excellent yield into the corresponding pharmaceutically acceptable salts by neutralization of said acid with the appropriate inorganic or organic base. The salts are administered in the same manner as the parent acid compounds. Suitable inorganic bases to form these salts include, for example, the hydroxides. carbonates, bicarbonates or alkoxides of the alkali metals or alkaline earth metals, for example, sodium, potassium, magnesium, calcium and the like. Suitable organic bases include the following amines; lower mono-, diand trialkylamines, the alkyl radicals of which contain up to three carbon atoms, such as methylamine, dimethylamine, trimethylamine, ethylamine, diand triethylamine, methylethylamine, and the like; mono-, diand trialkanolamines, the alkanol radicals of which contain up to three carbon atoms, such as mono-, diand triethanolamine; alkylene-diamines which contain up to six carbon atoms, such as hexamethylene diamine; cyclic saturated or unsaturated bases containing up to six carbon atoms, such as pyrrolidine, piperidine, morpholine, piperazine and their N-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine and N-(2-hydroxyethyl)piperidine, as well as pyridine. Furthermore, there may be mentioned the corresponding quaternary salts, such as the tetraalkyl (for example tetramethyl), alkyl-alkanol (for example methyl-trimethanol and trimethyl-monoethanol) and cyclic ammonium salts, for example the N-methyl-pyridinium, N-methyl-N-( 2-hydroxyethyl)- pyrrolidinium, N,N-dimethyl-morpholinium, N-methyl- N-(Z-hydroxyethyl)-morpholinium, N,N-dimethylpiperidinium and N-methyl-N-(2-hydroxyethyl)- piperidinium salts, which are characterized by an especially good water-solubility. In principle, however, there can be used all the ammonium salts which are physiologically compatible.

PGE is available by isolation from natural sources. for example. see B. Samuelsson, Angew. Chem. Int. Ed.. 4, 410 (1965). In addition. PGEg and its methyl ester are available by total synthesis. for example. see W. P. Schneider, Chem. Commun.. 304 (1969) and E. J. Corey et al., J. Amer. Chem. Soc.. 92, 397 (1970).

-Methylprostaglandin E and its corresponding methyl ester is described by E. W. Yankee and G. L. Bundy. J. Amer. Chem. Soc., 94. 3651 (1972).

16-Methylprostaglandin E and 16,16-dimethylprostaglandin E and their corresponding methyl esters are described in Belgian Pat. No. 782,822, published Aug. 16, 1972 and in West German Offenlegungsschrift No. 2,209.990. published Sept. 9, 1972.

Esters other than methyl of the aformentioned prostaglandin-type substances are prepared from the corresponding acids by known methods.

It should be understood that the prostaglandin-type substances of this invention, including the naturally occurring P65; and its lower alkyl esters, have two side chains which are in a trans relationship to each other. Furthermore, the double bond in the acid side chain of these substances has the cis configuration and the double bond in the side chain bearing the hydroxy group has the trans configuration.

Notwithstanding the preceding considerations the compounds of this invention having one or more asymmetric carbon atoms can exist in the form of various stereochemical isomers, i.e. racemates and enantiomorphs. [t is to be understood that such racemates and enantiomorphs are included within the scope of this invention.

When the aforementioned prostaglandin-type substances are employed according to the method of this invention, they are administered alone or in combination with an antiinflammatory agent with or without a pharmaceutical carrier. In the general embodiment of this invention the route of administration of the active agents is not critical. The prostaglandin derivative and the antiinflammatory agent are capable of being given perorally or parenterally, simultaneously or separately. The proportions of the prostaglandin substance, and the antiinflammatory agent if present, are determined by their solubilities, by the chosen route of administration and by standard biological practice. For many reasons oral administration is preferred. A convenient and practical pharmaceutical composition in solid form entails the prostaglandin substance, and if desired the antiinflammatory agent, containing such excipients as starch, lactose, sucrose, cellulose, certain types of clay. silica and flacoring and coating agents; see for example, Remington s Pharmaceutical Sciences, 14th ed., Mack Publishing Co., Easton, Penn, 1970 p. 1649.

Typical therapeutic compositions containing both the prostaglandin substance and the antiinflammatory agent in solid form comprise mixtures of these substances with indomethacin in a 1:10 to 1:5000 ratio by weight or with phenylbutazone or oxyphenylbutazone in a 1:100 to 1:10000 ratio.

Alternatively, the substances with or without the antiinflammatory agent are readily made up in the form of sterile solutions, emulsions and suspensions for oral administration. The solutions are prepared according to well known techniques; see for example, Remingtons Pharmaceutical Sciences, cited above, p. 1478. A convenient formulation for the water soluble salts of the acid specie noted above, is in the form of a sterile aqueous solution containing 0.001 to 10% by weight of LII the acid specie. Suitable suspending agents for preparing formulations of the mixture of the prostaglandin substance and the antiinflammatory agent include water soluble gums. for example. gum arabic. gum tragacanth and other pharmaceutically acceptable suspending or dispersing agent, for example, pectin, sodium alginate, alginic acid, acacia mucilage, carboxypolymethylene, sodium carboxymethyl cellulose, agar, bentonite. cetyl alcohol. gelatin. methyl cellulose, polyvinyl alcohol. polyvinylpyrrolidone, propylene glycol monostearate, sodium lauryl sulfate. sorbitan monooleate. stearyl alcohol. carrageenin. malt extract, oleyl alcohol, quillaja, tragacanth mucilage and the like.

Typical therapeutic composition in the form of sterile solutions. emulsions and suspensions comprise a mixture of the prostaglandin substance of this invention with indomethacin in 1:10 to 125000 ratio by weight and the active ingredients constituting 2 to 60% by weight of the composition.

The substances with or without the antiinflammatory agent may be administered parenterally. For parenteral administration, the substance (and agent) is dissolved or suspended in liquid carriers such as distilled water or oils of synthetic, animal, petroleum or vegetable origin, for example. soybean oil, sesame oil, mineral oil or propylene glycol, see also the suspending agents cited above. The usual preservatives and other ingredients used for pharmaceutical preparations for parenteral dose may also be incorporated. The concentration of the active agent in these preparations for parenteral use is selected to provide a generally useful composition.

In general, the pharmaceutical compositions are most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects. The prostaglandin substances are given preferably at a daily dose range of from about 0.001 meg to 10 mg/kg, although as aforementioned variations will occur. However. a dosage level that is in the range of from about 0.01 mcg to about 1.0 mg per kilo is most desirably employed in order to achieve efiective results. With respect to the prophylactic treatment of this invention, it is to be understood that the prostaglandin substance may be administered separately to a host receiving therapeutic treatment with an antiinflammatory agent or it may be combined with a therapeutic dose of the antiinflammatory agent and the combination administered in unit dosage form to the host in need of antiinflammatory therapy. Therapeutic doses for indomethacin usually range from about 0.1 to 10 mg/kg/day; for man the recommended peroral dose ranging from 0.5 to 4 mg/kg/day or a daily dose of about 25 to 200 mg. Therapeutic doses for phenylbutazone and oxyphenylbutazone usually range from 1 to 20 mg/kg/day; the recommended peroral dose for man ranging from 2 to 16 mg/kg/day or a daily dose of about to 800 mg.

The gastrointestinal side effect inhibiting property of the compositions of the present invention are demonstrable in standard pharmacological tests. For example, in procedures similar to the in vivo test described by Y. H. Lee et al.. cited above, for evaluating the effects of a test compound on indomethacin-induced ulcers in the rat, the compounds of formula 1 are shown to be effective, see Example 1.

The relevance of the Lee test to the clinical situation of indomethacin-induced ulcers is supported by the fact that. as N. O. Rothermich, J. Amer. Med. Assoc,

195, 531 1966) found a correlation between indomethacin dosage and the occurrence of ulcers in man, Lee found a similar correlation in the rat.

The finding that the prostaglandin substances of this anhydrides copolymerized with ethylene oxide. The

prostaglandin substances were given (0.2 ml) in a 0.2%

sodium carboxymethyl cellulose aqueous suspension.

The results of such a test for PGE to inhibit the ulcer lndomethacin was administered (0.5 ml) as an aque- H 0). Polysorbate 80 is a mixture of sorbitol and its invention inhibit ulcer formation induced by antiin- 5 formation induced by mg/kg i.p. of indomethucin flammatory agents at doses substantially less than those are given in the following table. For comparative purrequired for the inhibition of basal secretion of gastric poses the results obtained for propantheline bromide acid is illustrated by the fact that Y. H. Lee, et al., are also. included.

Dose No. of Ulcers Formed Compound (mg/kg. p.o.) Animals Mean S.E.M. 7( Inhibition ED,-,,I

None 22 10.3 l.4 P012 0.05 20 1.8 i 0.4*** 93 000x None 9 10.4 2 L3 propantheline 6.0 8 4.] i 0.9** 51 3.0 bromide prostaglandnis 9 (1973) reports that.PGE2 causfi The results show that PGE decreased the number of about a 50% 1nh1b1t1on of the basal secret1on of gastric mdomethacm-mduced ulcers, exhibltmg an ED of acid, expressed as gastrlc acid output in mrlhequlvaabout 0.008 mg/kg, p.o. over a period of five hours. By lents per five hours in the pylorus ligated rat, when the comparison propantheline bromme under the same PGE2 1S admlmstered perorally at a dose range Ofabout conditions was about 375 times less otent havin an 0.25 to 10 mg/kg to rats. While on the other hand P012 ED of 3 0 mg/k o p g at a peroral dose of about 0.008 mg/kg to rats is able to inhibit 50% of the expected ulcers from indomethacin, EXAMPLE 2 see Example 1. Th

e inception of substantlal diarrheal effect for the Furthermore, an unexpected advantage of the subsubstances of th1s mvent1on at dose levels h1gher than stances and combmatlons of the invention in that they th e aforementioned gastromtestmal side-effect 1nh1b1tdo not cause substantial d1arrhea at the aforemenmg doses 1s demonstrable in an in VlVO test in which the tloned gastromtestmal side effect-inhibiting doses 1s substance 15 given perorally in 0.2% SOCllUITl carboxydemonstrable m an in VIVO test in WhlCh the substance methylcellulose in water to female mice, the apparatus or combination is given perorally m 0.2% sodium car- 40 or absence of d1arrhea bemg recorded 60 mmutes later. boxymethyl cellulose in water to female mice or rats, th The results of such as tested for PGE are shown in the e appearance or absence of d1arrhea bemg recorded f ollowmg table. 60 mmutes later.

The following examples illustrate further this invention' Diarrhea-producing Action of PGE2 in Fed-mouse Diarrhea] Activity EXAMPLE 1 Dose No. of Animals 7: of Animals ED -,,I /1 .1 By following the procedure of Lee et al., c1ted above, mg g p O for the production of the indomethacin-induced ulcer 2 43 in rats, the property of the prostaglandin-type sub- 27 3/10 30 stances of this invention to inhibit such ulcers is readily demonstrated. More specifically: male albino rats (l70l90 g; Sprague-Dawley strain, Canadian Breed- Since the above ED for diarrheal effect of PGE is ing Laboratories), caged individually, were fasted 24 hr well above the therapeutic dose of PGE according to with free access to water until the start of the experithe method of this invention, this experiment indicates ment. Indomethacin was given intraperitoneally. The that the prostaglandin substances of this invention can animals were killed5 hr later and the ulcer formation in be administered at doses that do not elicit the side the glandular portion of the stomach determined. The effect of diarrhea. prostaglandin substance was administered perorally immediately after the indomethacin. The percent inhi- EXAMPLE 3 bition of ulcer formation versus the semilogarithm of The inhibitory effect of the prostaglandin substances the dose (mg/kg) was plotted and the dose at which of this invention on the formation of phenylbutazone- 50% inhibition occurred (ED was read from the induced ulcers in rats is demonstrable by the method graph. exemplified herein by the choice of PGE as the prosta- Analysis of variance and regression study were used glandin substance. in the evaluation of the data. Male albino rats (-150 g; Sprague Dawley strain, Canadian Breeding Laboratories), caged individually were fasted 24 hours with free access to water until the start of the experiment. PGE was given orally in a suspension of 0.2 ml of 0.2% sodium carboxymethylcellulose in water. Thirty minutes later phenylv butazone (300 mg/kg) in 0.4 ml of an aqueous suspension (1 drop of polysorbate 80 per 14 ml off-1 was given orally. The animals were killed 18 hours later and the ulcer formation (i.e. number of ulcers) in the glandular portion of the stomach determined. The percent inhibition of ulcer formation versus the semilogarithm of the dose (mg/kg) was plotted and the dose at which 50% inhibition occurred (ED was read from the graph.

The results of a test according to the preceding method is summarized in the following table.

Ulcers Formed EDS" Test Compound (mg/kg. p.o.) Animals Mean 1 S.E.M. 72 Inhibition rng/kg None 5.4 i 1.0 PGE: 3.0 10 0.6 i 0.2 89 0.8

The results show that PGE decreases the number of phenylbutazone-induced ulcers, exhibiting an ED of about 0.8 mg/kg, p.o. over an 18 hr. period.

By replacing phenylbutazone with an equivalent amount of oxyphenylbutazone in the procedure of this example, the inhibitory effect of the prostaglandin substances of this invention on the formation of oxyphenylbutazone-induced ulcers in rats is demonstrated.

EXAMPLE 4 a. The following tablet compositions are illustrative of such compositions of this invention:

The prostaglandin substance, PGE (0.15 g) is mixed with 197.85 g lactose, 44 g microcrystalline cellulose, 4 g stearic acid and 4 g of finely divided silica (Cabosil). The mixture is granulated with addition of a small amount of ethyl alcohol, dried, milled, and compressed into tablets weighing 250 mg each or filled into capsules in amounts of 250 mg each, to make 1000 tablets or capsules containing 0.15 mg of the active ingredient per tablet or capsule.

in same manner but using 1.0 g of PGE and 197 g of lactose, together with the same amounts of microcrystalline cellulose, stearic acid and silica as above, 1000 tablets or capsules containing 1.0 mg of the active ingredient per tablet or capsule are obtained.

Again in the same manner but adding 25 g of indomethacin and using 0.025 g of the prostaglandin substance and 172.975 g of lactose together with the same amount of microcrystalline cellulose, stearic acid and silica as above, 1000 tablets or capsules containing 0.025 mg of the prostaglandin substance in combination with 25 mg of indomethacin are obtained.

Again in the same manner but adding 40 g of phenylbutazone or oxyphenylbutazone and using 0.1 g of the prostaglandin substance, 157.9 g of lactose together with the same amounts of microcrystalline cellulose, stearic acid and silica as above, 1000 tablets or capsules containing 0.1 mg of the prostaglandin substance in combination with 40 mg of phenylbutazone or oxyphenylbutazone are obtained.

Again in the same manner but adding 40 g of phenylbutazone or oxyphenylbutazone and using 0.05 g of lo-methyl PGE as the prostaglandin substance and using 157.95 g of lactose together with the same amounts of microcrystalline cellulose, stearic acid and of such compositions of this invention.

The prostaglandin substance, 15-methyl PGE (50 mg), is dissolved in pyrogen-free water (900 ml) by adjusting the pH to 7.5-8.5 with sodium hydroxide solution and adding sufficient sodium chloride or sodium citrate or glucose to make the solution isotonic. A preservative such as 0.1 percent weight by volume of methylparaben and 0.015 percent weight by volume of propylparaban or 0.5 percent weight by volume of chlorobutanol is added, the solution is made up to 1000 ml, sterilized by filtration or autoclaving, and filled into sterile ampoules or vials, to make a solution of parenteral or oral administration containing 0.05 mg of the active ingredient per milliliter.

Again in the same manner, but using, instead of sodium hydroxide, lithium, potassium, calcium or ammonium hydroxide, or aqueous solutions of methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, methylethylamine, mono-, di-, or triethanolamine, ethylenediamine, hexamethylenediamine, pyrrolidine, piperidine, morpholine, piperazine, N-methylmorpholine, N-( 2-hydroxyethyl )piperidine, or pyridine, or quaternary bases containing the tetramethyl, methyltriethanol, or trimethylmonoethanol ammonium ion, or the N-methylpyridinium, N-methyl- N-(2-hydroxyethyl)-pyrrolidinium. N,N-dimethylmorpholinium, N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-dimethylpiperidinium, or N-methyl-N- (Z-hydroxyethyl)-piperidinium ions, the corresponding salts of 2-(3-hydroxy-3-methyloctyl)-5-oxocyclopentaneheptanoic acid are also obtained.

Again in the same manner but replacing the above prostaglandin substance by the same weight of another prostaglandin substance of thisinvention, corresponding liquid compositions for the other substances are obtained.

The prostaglandin substance. 16.16-dimethyl PGE -(0.03 g) and indomethacin (40.0 g) are sterilized sepac. The following suspension composition is illustrative of such compositions of this invention.

The prostaglandin substance, PGE (0.20 g) and indomethacin (40.0 g) each are micronized to below 40p. particle size. The two active ingredients are then mixed with 200 ml of water and 140 ml of sugar syrup. Methylparaben (0.625 g) and propylparaben (0.125 g) are dissolved in 100 ml of glycerin with the aid of heat and sodium alginate (25.0 g) is added to the glycerin solution. The glycerin mixture is then added to the above mixture of the active ingredients. The resulting mixture is stirred until an even dispersion is obtained. Flavourings may optionally be added at this point. Thereafter, the suspension is diluted with sufficient water to a volume of 1000 ml. The resulting suspension for oral administration contains 0.20 mg/ ml of the prostaglandin substance and 40.0 mg/ml of indomethacin.

I claim:

l. A method of reducing the incidence of gastrointestinal side effects in a mammal during the treatment of inflammatory conditions with an antiinfiammatory agent, which comprises administering to said mammal a gastrointestinal side effect inhibiting amount within the range of about 0.01 microgram to about 1 milligram per kilogram of a prostaglandin substance selected from the group consisting of l5-methylprostaglandin E l6methylprostaglandin E and 16,16-dimethylprostaglandin E the corresponding lower alkyl esters thereof and the pharmaceutically acceptable salts thereof.

2. A pharmaceutical composition in unit dosage form for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose within the range of about 0.01 microgram to about 1 milligram per kilogram of a prostaglandin substance selected from the group consisting of l5-methylprosta- 10 glandin E l-methylprostaglandin E and 16,16-dimethylprostaglandin E the corresponding lower alkyl esters thereof and the pharmaceutically acceptable salts thereof; together with a therapeutic dose of an antiinfiammatory drug and a pharmaceutically acceptable carrier.

3. The method of claim 1 wherein said anti-inflammatory agent is selected from the group consisting of indomethacin, phenylbutazone, oxyphenylbutazone, or aspirin.

4. The composition of claim 2 wherein said anti-inflammatory drug is selected from the group consisting of indomethacin, phenylbutazone, oxyphenylbutazone, or aspirin.

5. The method of claim 1 wherein said anti-inflammatory agent is useful for the treatment of arthritic and rheumatic diseases.

6. The composition of claim 2 wherein said anti-inflammatory drug is useful for the treatment of arthritic and rheumatic diseases.

7. A method of reducing the incidence of gastrointestinal side effects in a mammal during the treatment of inflammatory conditions with an antiinfiammatory agent, which comprises administering to said mammal a gastrointestinal side effect inhibiting amount within the range of about 0.01 microgram to about 1 milligram per kilogram of l6,l6-dimethyl PGE during said treatment.

8. A pharmaceutical composition in unit dosage form for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose within the range of about 0.01 microgram to about 1 milligram per kilogram of l6,l6-dimethyl PGE and a therapeutic dose of an antiinfiammatory agent. 

1. A METHOD OF REDUCING THE INCIDENCE OF GASTROINTESTINAL SIDE EFFECTS IN A MAMMAL DURING THE TREATMENT OF INFLAMMATORY CONDITIONS WITH AN ANTIINFLAMMATORY AGENT, WHICH COMPRISES ADMINISTERING TO SAID MAMMAL A GASTROINTESTINAL SIDE EFFECT INHIBITING AMOUNT WITHIN THE RANGE OF ABOUT 0.01 MICROGRAM TO ABOUT 1 MILLIGRAM PER KILOGRAM OF A POSTAGLANDIN SUBSTANCES SELECTED FROM THE GROUP CONSISTING OF 15-METHYLPROSTAGLANDIN E2, 16-METHYLPROSTAGLANDIN E2 AND 16, 16-DIMETHYLPROSTAGLANDIN E2, THE CORRESPONDING LOWER ALKYL ESTERS THEREOF AND THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.
 2. A pharmaceutical composition in unit dosage form for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose within the range of about 0.01 microgram to about 1 milligram per kilogram of a prostaglandin substance selected from the group consisting of 15-methylprostaglandin E2, 16-methylprostaglandin E2 and 16,16-dimethylprostaglandin E2 the corresponding lower alkyl esters thereof and the pharmaceutically acceptable salts thereof; together with a therapeutic dose of an antiinflammatory drug and a pharmaceutically acceptable carrier.
 3. The method of claim 1 wherein said anti-inflammatory agent is selected from the group consisting of indomethacin, phenylbutazone, oxyphenylbutazone, or aspirin.
 4. The composition of claim 2 wherein said anti-inflammatory drug is selected from the group consisting of indomethacin, phenylbutazone, oxyphenylbutazone, or aspirin.
 5. The method of claim 1 wherein said anti-inflammatory agent is useful for the treatment of arthritic and rheumatic diseases.
 6. The composition of claim 2 wherein said anti-inflammatory drug is useful for the treatment of arthritic and rheumatic diseases.
 7. A method of reducing the incidence of gastrointestinal side effects in a mammal during the treatment of inflammatory conditions with an antiinflammatory agent, which comprises administering to said mammal a gastrointestinal side effect inhibiting amount within the range of about 0.01 microgram to about 1 milligram per kilogram of 16,16-dimethyl PGE2 during said treatment.
 8. A pharmaceutical composition in unit dosage form for treating inflammatory conditions comprising a combination of a gastrointestinal side effect-inhibiting dose within the range of about 0.01 microgram to about 1 milligram per kilogram of 16,16-dimethyl PGE2 and a therapeutic dose of an antiinflammatory agent. 